2020 — 2021 |
Shen, Mark D |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Cerebrospinal Fluid Abnormalities in Neurodevelopmental Disorders @ Univ of North Carolina Chapel Hill
Cerebrospinal fluid (CSF) circulation is essential for removing neuroinflammatory proteins through a process that involves the brain's newly discovered lymphatic system. Circulating CSF also delivers growth factors that help regulate brain development. Aberrant CSF circulation can result in a pathogenic buildup of neuroinflammatory proteins and alter brain growth. CSF serves to link the central nervous and immune systems, which are dysfunctional in neurodevelopmental disorders (NDDs). In three independent cohorts, our team was the first to report that children with idiopathic autism spectrum disorder (iASD) have increased CSF volume surrounding the brain (extra-axial CSF; EA-CSF) from 6 months to 4 years of age (Shen et al., 2013; 2017; 2018). Excessive EA-CSF was detectable at 6 months of age (prior to onset of the defining behavioral symptoms of ASD), was correlated with severity of specific later symptoms, and predicted later diagnosis. We extended this research to single-gene NDDs with varying degrees of overlapping and distinct symptoms with iASD and now present preliminary data showing that these single-gene NDDs also have excessive EA-CSF volume. Our preliminary data also indicate that rodent models of these NDDs have excessive EA-CSF, similar to the patient populations, and reduced CSF circulation. Our new observations suggest that excessive EA-CSF may be a potential biomarker of a shared pathophysiological process in multiple NDDs. This project will prospectively study infant cohorts of multiple NDDs, and corresponding mouse models, to examine the overarching hypothesis that excessive EA-CSF volume and impaired CSF circulation result in an accumulation of neuroinflammatory proteins and are related to aberrant brain and behavior development. This proposal will: [1] leverage resources from ongoing NIH-funded MRI studies of children with NDDs; [2] enlist a multidisciplinary team with expertise in CSF abnormalities in children with NDDs, neurophysiology of NDD mouse models, mouse neuroimaging, infant neuroimaging, clinical phenotyping of infants with NDDs, and the lymphatic system; and [3] utilize all three UNC IDDRC research cores to address the following aims: Aim 1: To elucidate potential mechanisms underlying excessive EA-CSF in selected NDD model mice. Aim 2: To examine relationships between EA-CSF volume, CSF circulation, and brain and behavior features in children with etiologically-distinct NDDs. This research will expand our knowledge of a new phenomenon ? aberrant CSF physiology in the early development of NDDs ? by examining the mechanisms and brain and behavior correlates in NDDs and corresponding rodent models, to provide important insights for: development of targeted treatments, potential predictive biomarkers of later disease progression, and knowledge about CSF pharmacodynamics relevant to upcoming clinical trials in NDDs using intrathecal CSF drug delivery. 1
|
0.988 |
2021 |
Schwichtenberg, Amy J [⬀] Shen, Mark D |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Sleep, the Glymphatic System, and Social Communication Development
Project Summary: Sleep plays a crucial role in several biological processes including nervous, immune, and endocrine systems. One critical function of sleep is the removal of neuronal metabolic waste via cerebrospinal fluid (CSF) circulation within the glymphatic system (GS). The GS is a brain-wide system with functions that are enhanced during sleep to clear inflammatory proteins and metabolites. Recent advancements in our understanding of the GS highlight its role in neurodevelopmental disorders and developmental risk. Specifically, Shen and colleagues reported excessive CSF in the subarachnoid space (extra-axial CSF; EA-CSF) as an early marker of autism and a correlate of developmental risk and sleep problems. MRI extracted EA-CSF volume can serve as a non-invasive marker of GS anatomy. Although the precise mechanisms leading to excessive EA-CSF are unknown, it is known that GS processes are enhanced during sleep. Developmental periods marked by high sleep need (e.g., infancy), likely reflect an increased need for the clearance of neuronal metabolic waste. Disruptions in sleep, during early development likely influence GS function and have the potential to contribute to neurodevelopmental risk and resilience. This study aims to elucidate the relations between sleep dysregulation, EA-CSF growth patterns in infancy, and a known area of concern for children with autism - social communication development. Within this study, we will index volumetric EA-CSF data from the community sample followed within the Baby Connectome Project (U01MH110274) with high-resolution structural MRI scans from 1 to 26 months of age. The hybrid accelerated longitudinal design of this dataset is well-suited for developmental pattern estimation. With a newly-developed automated MRI pipeline, we will model EA-CSF patterns over the first two years of life. To describe the relations between EA-CSF development and sleep dysregulation (Aim 1), we will compare EA-CSF growth patterns across two groups of infants ? those with regulated (S-REG) and dysregulated (S-DYS) sleep. We predict a group by age interaction, with the S-DYS group showing a growth pattern of EA-CSF over time that is significantly increased relative to the S- REG group. We believe the greater increase of EA-CSF in the S-DYS group may reflect an imbalance of CSF circulation/clearance. To assess how sleep dysregulation and EA-CSF growth patterns relate to social communication development (Aim 2), we will complete another set of group-based analyses to assess if lower social communication scores are present in (1) the S-DYS group and (2) infants with atypical EA-CSF growth patterns. The overarching goal of this line of work is to inform mechanistic pathways between sleep dysregulation and neurodevelopmental risk. This study focuses on EA-CSF, based on its known connections to sleep, autism, and other indices of developmental risk. Using a developmental psychopathology approach, this study provides crucial first steps in translating how EA-CSF growth within a community sample can inform our understanding of a potential neuroanatomical marker of social communicative risk and resilience.
|
0.961 |